1. Field of the Invention
The invention relates to dipeptide amides which are useful as analgesics.
2. Description of the Prior Art
Coy and Kastin U.S. Pat. No. 4,127,535 describes
H-Tyr-X-Y PA1 wherein: X is a chiral residue of a D-amino acid selected from the group consisting of D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-trytophan, D-serine, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-proline[,] D-aspartic acid, D-asparagine, D-lysine, D-arginine and D-histidine; and Y is selected from the group consisting of hydroxy, amino, loweralkylamino, diloweralkylamino and lower alkoxy PA1 useful as analgesic, tranquilizer, sedative, hypnotic, anti-depressant[,] prolactin releasing and growth hormone releasing agents PA1 R.sub.2 taken together with R.sub.3 is dimethylene, trimethylene or tetramethylene; PA1 R.sub.4 is (CH.sub.2).sub.n Y, wherein n is an integer from 2 through 10 and Y is phenyl or phenyl substituted by fluoro, chloro, methyl or methoxy; and PA1 R.sub.5 is hydrogen, alkyl of one to five carbon atoms or (CH.sub.2).sub.n Y as defined for R.sub.4 ; PA1 or a pharmaceutically acceptable acid addition salt thereof. PA1 Tyr represents L-tyrosyl, PA1 Pro represents L-prolyl, PA1 Me represents methyl, and PA1 Ph represents phenyl.
which are stated to be
and which are designated in the illustrative examples as derivatives of .beta.-lipotropin fragment 61-62. Example 34 specifically describes D-Ala.sup.2 -.beta.-lipotropin fragment 61-62 amide by name and method of preparation but does not describe any chemical or biological properties thereof.
McGregor (et al., Life Sciences, vol. 23, no. 13, pp. 1371-1378, 1978) describes H-Tyr-D-Ala-NH.sub.2 (D-Ala.sup.2 -.beta.-lipotropin fragment 61-62 amide) and shows that it is greater than 10 times less potent intravenously and 200 times less potent intraventricularly in the tail flick test for analgesia in the rat, and binds to the opiate receptor in rat brain membranes with 830 times less affinity, than morphine.
Roques (et al., European Journal of Pharmacology, vol. 60, pp. 109-110, 1979) describes EQU HTyrD-AlaNH(CH.sub.2).sub.2 NH(CH.sub.2).sub.2 Phenyl,
which was less then 1% as potent as Met-enkephalin in both the guinea pig ileum and mouse vas deferens tests.